DESCRIPTION: (Applicant's Abstract) Diabetic retinopathy substantially contributes to the morbidity of type 2 diabetes mellitus and is a strong predictor of subsequent, often early, mortality in those with diabetes. Susceptibility to type 2 diabetes has long been known to have a substantial genetic component. Not only does diabetes aggregate in families, but so do its complications. Preliminary results demonstrate an 8.3 fold increased risk for retinopathy in diabetic siblings of a diabetic with no retinopathy. It is likely that diabetes susceptibility alleles impact the clinical courses of the disease and development of retinopathy. It is also plausible that other genes influence susceptibility to retinopathy, but exert their influence only after the development of diabetes. To determine the contribution of genetic factors to diabetic retinopathy, 1,000 Mexican Americans with type 2 diabetes distributed in 750 sibling pairs will undergo detailed eye examinations on 2 occasions (2.5 years apart). Examinations will include stereoscopic fundus photography and scoring according to standard protocols. Except for the retinal examinations, these individuals have been and are being characterized in ongoing studies in Starr County, Texas. These characterization includes genotypes at markers spanning the entire genome at an average distance of 8 to 10 centi-Morgans. All marker data will be available prior to the completion of the first round of retinal examinations. Documentation of the presence and severity of diabetic retinopathy in this sibling pair genotype resource and an additional confirmatory set of 200 individuals with diabetes will permit: 1) Determining the sibling pair concordance for retinopathy, 2) Localizing retinopathy susceptibility loci based on two-point and multi- point sibling pair linkage analysis, and 3) Identification of variation by DNA sequence scanning of genes in linked regions impacting on the presence and development of retinopathy. The end result will be improved understanding of mechanisms and exploitable pathways for moving retinopathy treatment from palliative to preventive.